Impairment of preimplantation and postimplantation embryonic development through intrinsic apoptotic processes by ginsenoside Rg1in vitroandin vivo

Abstract

Ginsenoside Rg1, which is the most abundant compound found in Asian ginseng (Panax ginseng), has demonstrated various pharmacological actions, including neuroprotective, immune-stimulatory, and antidiabetic effects. Pregnant women, especially in the Asian community, consume ginseng as a nutritive supplement. Thus, the effects of ginsenoside-Rg1 on embryonic development need to be investigated, such as in a mouse model. As previous investigations have found that ginsenoside Rg1 appears to either trigger or prevent apoptosis in different cell lines, the effects of this agent on apoptosis remain to be clarified. In this study, we investigated whether ginsenoside Rg1 exerts a hazardous effect on mouse blastocysts and/or affects subsequent embryonic development in vitro and in vivo. Blastocysts treated with 25-100 μM ginsenoside Rg1 exhibited significant induction of apoptosis and a corresponding decrease in the inner cell mass (ICM) cell number. Importantly, the implantation rate was lower among ginsenoside Rg1-treated blastocysts compared to untreated controls. Moreover, embryo transfer assays revealed that blastocysts treated with 100 μM ginsenoside Rg1 exhibited increased resorption of postimplantation embryos and decreased weight among surviving fetuses. In vivo, intravenous injection of mice with ginsenoside Rg1 (2, 4, or 6 mg/kg body weight/day) for 4 days was associated with increased apoptosis of blastocyst-stage embryos and negatively impacted early embryonic development. Further experiments revealed that these effects may reflect the ability of ginsenoside Rg1 to trigger oxidative stress-mediated intrinsic apoptotic signaling. Our in vitro results indicate that ginsenoside Rg1 treatment increases intracellular oxidative stress, decreases mitochondrial membrane potential, increases the Bax/Bcl-2 ratio, and activates caspase-9 and caspase-3, but not caspase-8. Taken together, our study results strongly suggest that ginsenoside Rg1 induces apoptosis and impairs the early preimplantation and postimplantation development of mouse embryos, both in vitro and in vivo.

Berberine impairs embryonic development in vitro and in vivo through oxidative stress‐mediated apoptotic processes

“…TE cells further develop to form a sphere of epithelial cells surrounding the ICM and blastocoel, contributing to placenta formation, and are required for development of the mammalian conceptus . Previous studies and our recent investigation have found that a reduction in the TE cell lineage suppresses implantation and embryonic viability . Our data showed that berberine‐induced embryonic cell death occurs only in the TE and not ICM, also leading to decreased implantation and postimplantation development in mice (Figures ).…”

“…46 Previous studies and our recent investigation have found that a reduction in the TE cell lineage suppresses implantation and embryonic viability. [30][31][32][47][48][49] Our data showed that berberine-induced embryonic cell death occurs only in the TE and not ICM, also leading to decreased implantation and postimplantation development in mice (Figures 1-4). Our investigation of the regulatory mechanisms of berberineinduced apoptosis in mouse blastocyst revealed that apoptotic processes triggered by berberine were initiated through generation of high levels of intracellular ROS ( Figure 6).…”

“…In preimplantation stage embryonic development, apoptotic processes do not occur from fertilization to the blastocyst stage . Some teratogens, however, trigger apoptotic processes prior to the blastocyst stage, and could therefore exert hazardous effects on embryogenesis or embryo development . In this investigation, we analyzed whether the apoptotic inducer, berberine, exerts injurious effects on preimplantation embryonic development in mouse early stage embryos.…”

“…25 Some teratogens, however, trigger apoptotic processes prior to the blastocyst stage, and could therefore exert hazardous effects on embryogenesis or embryo development. [26][27][28][29][30][31] In this investigation, we analyzed whether the apoptotic inducer, berberine, exerts injurious effects on preimplantation embryonic development in mouse early stage embryos. The effects of berberine on subsequent postimplantation developmental injury in vitro and in vivo, and detailed regulatory mechanisms, were also examined.…”

Dosage‐related beneficial and deleterious effects of ginsenoside Rb1 on mouse oocyte maturation and fertilization and fetal development

“…Microenvironment factors or status, including oxygen concentration, temperature, and glucose content could affect oocyte growth, maturation, and/or viability . Multiple studies have established that chemical or physical teratogens induce cell death in oocyte maturation or preimplantation stage embryos, with hazardous consequences on embryonic development . Importantly, a recent investigation by our group showed that GRb1 triggers apoptosis through ROS‐mediated signaling to impair embryo development in mouse blastocysts .…”